On the evolutionary trail of MagRs.

Magnetic sense, or termed magnetoreception, has evolved in a broad range of taxa within the animal kingdom to facilitate orientation and navigation. MagRs, highly conserved A-type iron-sulfur proteins, are widely distributed across all phyla and play essential roles in both magnetoreception and iron-sulfur cluster biogenesis. However, the evolutionary origins and functional diversification of MagRs from their prokaryotic ancestor remain unclear. In this study, MagR sequences from 131 species, ranging from bacteria to humans, were selected for analysis, with 23 representative sequences covering species from prokaryotes to Mollusca, Arthropoda, Osteichthyes, Reptilia, Aves, and mammals chosen for protein expression and purification. Biochemical studies revealed a gradual increase in total iron content in MagRs during evolution. Three types of MagRs were identified, each with distinct iron and/or iron-sulfur cluster binding capacity and protein stability, indicating continuous expansion of the functional roles of MagRs during speciation and evolution. This evolutionary biochemical study provides valuable insights into how evolution shapes the physical and chemical properties of biological molecules such as MagRs and how these properties influence the evolutionary trajectories of MagRs.

Mitochondrial targeting sequence of magnetoreceptor MagR: More than just targeting.

Iron-sulfur clusters are essential cofactors for proteins involved in various biological processes, such as electron transport, biosynthetic reactions, DNA repair, and gene expression regulation. Iron-sulfur cluster assembly protein IscA1 (or MagR) is found within the mitochondria of most eukaryotes. Magnetoreceptor (MagR) is a highly conserved A-type iron and iron-sulfur cluster-binding protein, characterized by two distinct types of iron-sulfur clusters, [2Fe-2S] and [3Fe-4S], each conferring unique magnetic properties. MagR forms a rod-like polymer structure in complex with photoreceptive cryptochrome (Cry) and serves as a putative magnetoreceptor for retrieving geomagnetic information in animal navigation. Although the N-terminal sequences of MagR vary among species, their specific function remains unknown. In the present study, we found that the N-terminal sequences of pigeon MagR, previously thought to serve as a mitochondrial targeting signal (MTS), were not cleaved following mitochondrial entry but instead modulated the efficiency with which iron-sulfur clusters and irons are bound. Moreover, the N-terminal region of MagR was required for the formation of a stable MagR/Cry complex. Thus, the N-terminal sequences in pigeon MagR fulfil more important functional roles than just mitochondrial targeting. These results further extend our understanding of the function of MagR and provide new insights into the origin of magnetoreception from an evolutionary perspective.

Filamentous morphology engineering of bacteria by iron metabolism modulation through MagR expression.

The morphology is the consequence of evolution and adaptation. Escherichia coli is rod-shaped bacillus with regular dimension of about 1.5 µm long and 0.5 µm wide. Many shape-related genes have been identified and used in morphology engineering of this bacteria. However, little is known about if specific metabolism and metal irons could modulate bacteria morphology. Here in this study, we discovered filamentous shape change of E. coli cells overexpressing pigeon MagR, a putative magnetoreceptor and extremely conserved iron-sulfur protein. Comparative transcriptomic analysis strongly suggested that the iron metabolism change and iron accumulation due to the overproduction of MagR was the key to the morphological change. This model was further validated, and filamentous morphological change was also achieved by supplement E. coli cells with iron in culture medium or by increase the iron uptake genes such as entB and fepA. Our study extended our understanding of morphology regulation of bacteria, and may also serves as a prototype of morphology engineering by modulating the iron metabolism.

Unexpected divergence in magnetoreceptor MagR from robin and pigeon linked to two sequence variations.

Birds exhibit extraordinary mobility and remarkable navigational skills, obtaining guidance cues from the Earth's magnetic field for orientation and long-distance movement. Bird species also show tremendous diversity in navigation strategies, with considerable differences even within the same taxa and among individuals from the same population. The highly conserved iron and iron-sulfur cluster binding magnetoreceptor (MagR) protein is suggested to enable animals, including birds, to detect the geomagnetic field and navigate accordingly. Notably, MagR is also implicated in other functions, such as electron transfer and biogenesis of iron-sulfur clusters, raising the question of whether variability exists in its biochemical and biophysical features among species, particularly birds. In the current study, we conducted a comparative analysis of MagR from two different bird species, including the migratory European robin and the homing pigeon. Sequence alignment revealed an extremely high degree of similarity between the MagRs of these species, with only three sequence variations. Nevertheless, two of these variations underpinned significant differences in metal binding capacity, oligomeric state, and magnetic properties. These findings offer compelling evidence for the marked differences in MagR between the two avian species, potentially explaining how a highly conserved protein can mediate such diverse functions.

GDF-15 at admission predicts cardiovascular death, heart failure, and bleeding outcomes in patients with CAD.

AIMS: We aimed to investigate the independent associations between growth differentiation factor 15 (GDF-15) level at admission and cardiovascular (CV) death, thrombotic events, heart failure (HF), and bleeding outcomes in patients with coronary artery disease (CAD). METHODS AND RESULTS: We measured the plasma concentrations of GDF-15 centrally in patients from the BIomarker-based Prognostic Assessment for patients with Stable angina and acute coronary Syndrome (BIPass) registry, which consecutively enrolled patients with CAD from November 2017 to September 2019 at five tertiary hospitals in China. The outcomes included CV death, thrombotic events [myocardial infarction (MI) and ischaemic stroke], HF events [acute HF during hospitalization and hospitalization for HF post-discharge (A/H HF) and cardiogenic shock], and bleeding outcomes [non-coronary artery bypass grafting-related major bleeding and clinically significant bleeding (CSB)] during the 12 month follow-up period after hospitalization. Among 6322 patients with CAD {65.4% male, median age 63.7 [inter-quartile range (IQR)] 56.0-70.1 years}, the median concentration of plasma GDF-15 at admission was 1091 (IQR 790.5-1635.0) ng/L. Higher concentrations of GDF-15 were associated with an increased risk of CV death [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.35-2.88, P < 0.001], A/H HF (HR 2.69, 95% CI 1.92-3.77, P < 0.001), cardiogenic shock (HR 1.46, 95% CI 1.04-2.05, P = 0.029), and CSB (HR 1.48, 95% CI 1.22-1.79, P < 0.001), but not for MI or stroke, after adjusting for clinical risk factors and prognostic biomarkers. Adding GDF-15 to the model with risk factors and biomarkers improved the net reclassification for CV death, A/H HF, cardiogenic shock, and CSB. CONCLUSIONS: In patients with CAD, admission levels of GDF-15 were associated with an increased 1 year risk of CV death, HF, and bleeding outcomes, but not with thrombotic events. GDF-15 may be a prognostic biomarker for CV death, HF, and bleeding outcomes and could be used to refine the risk assessment of these specific clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04044066.

Towards magnetism in pigeon MagR: Iron- and iron-sulfur binding work indispensably and synergistically.

The ability to navigate long distances is essential for many animals to locate shelter, food, and breeding grounds. Magnetic sense has evolved in various migratory and homing species to orient them based on the geomagnetic field. A highly conserved iron-sulfur cluster assembly protein IscA is proposed as an animal magnetoreceptor (MagR). Iron-sulfur cluster binding is also suggested to play an essential role in MagR magnetism and is thus critical in animal magnetoreception. In the current study, we provide evidence for distinct iron binding and iron-sulfur cluster binding in MagR in pigeons, an avian species that relies on the geomagnetic field for navigation and homing. Pigeon MagR showed significantly higher total iron content from both iron- and iron-sulfur binding. Y65 in pigeon MagR was shown to directly mediate mononuclear iron binding, and its mutation abolished iron-binding capacity of the protein. Surprisingly, both iron binding and iron-sulfur binding demonstrated synergistic effects, and thus appear to be integral and indispensable to pigeon MagR magnetism. These results not only extend our current understanding of the origin and complexity of MagR magnetism, but also imply a possible molecular explanation for the huge diversity in animal magnetoreception.

Analysis of the correlation between sleep and mental health among primary and secondary school students in Shandong Province / 中国学校卫生

Objective@#To investigate the sleep and mental health status of adolescents in Shandong Province, to explore the correlation between sleep and mental health, so as to provide a basis for adolescent physical and mental health management.@*Methods@#From February to March 2023,a multistage stratified whole cluster sampling method was used to randomly select 3 cities in Shandong Province, one urban area and one township in each city, one junior high school and one senior high school in the urban area and the township, respectively, and then 4 classes were randomly selected from each grade level of each school, and all 3 667 students in the classes were surveyed by using the Pittsburgh Sleep Quality Index Scale (PSQI) short form and the Chinese Middle School Students Mental Health Inventory (MMHI-60).@*Results@#The prevalence of sleep deprivation among adolescents in Shandong Province was 37.44%, and the detection rate of psychological problems was 46.41%. Adolescent psychology could be divided into four latent categories:psychological immune group (39.6%), psychological low risk group (12.2%), psychological medium risk group (13.2%) and psychological high risk group (35.0%). Multifactorial Logistic regression analyses showed that gender, school year, sleep duration and sleep quality were influencing factors for the psychological latent categories ( OR =1.39-9.55, P < 0.05 ), and that adolescents with sleep deprivation and poor sleep quality were more inclined to be classified as being in the psychological medium and high risk groups.@*Conclusions@#The sleep and mental health of adolescents in Shandong Province is not very good. Comprehensive prevention and control of psychological problems should not only focus on personality and psychological characteristics, but also need to be combined with the sleep condition of adolescents.

Transcriptomic analysis of genes related to alkaloid biosynthesis and the regulation mechanism under precursor and methyl jasmonate treatment in Dendrobium officinale.

Dendrobium officinale is both a traditional herbal medicine and a plant of high ornamental and medicinal value. Alkaloids, especially terpenoid indole alkaloids (TIAs), with pharmacological activities are present in the tissues of D. officinale. A number of genes involved in alkaloid biosynthetic pathways have been identified. However, the regulatory mechanisms underlying the precursor and methyl jasmonate (MeJA)-induced accumulation of alkaloids in D. officinale are poorly understood. In this study, we collected D. officinale protocorm-like bodies (PLBs) and treated them with TIA precursors (tryptophan and secologanin) and MeJA for 0 (T0), 4 (T4) and 24 h (T24); we also established control samples (C4 and C24). Then, we measured the total alkaloid content of the PLBs and performed transcriptome sequencing using the Illumina HiSeq 2,500 system. The total alkaloid content increased significantly after 4 h of treatment. Go and KEGG analysis suggested that genes from the TIA, isoquinoline alkaloid, tropane alkaloid and jasmonate (JA) biosynthetic pathways were significantly enriched. Weighted gene coexpression network analysis (WGCNA) uncovered brown module related to alkaloid content. Six and seven genes related to alkaloid and JA bisosynthetic pathways, respectively, might encode the key enzymes involved in alkaloid biosynthesis of D. officinale. Moreover, 13 transcription factors (TFs), which mostly belong to AP2/ERF, WRKY, and MYB gene families, were predicted to regulate alkaloid biosynthesis. Our data provide insight for studying the regulatory mechanism underlying TIA precursor and MeJA-induced accumulation of three types of alkaloids in D. officinale.

Four-way decomposition of effect of cigarette smoking and body mass index on serum lipid profiles.

OBJECTIVE: Smoking and obesity are established risk factors of dyslipidemia, however, the interplay between them has not been well studied. This study aims to explore the joint effect of smoking and body mass index (BMI) on serum lipid profiles. METHODS: The study consisted of 9846 Chinese adults (mean age = 49.9 years, 47.6% males, 31.2% ever smokers), based on the China Health and Nutrition Survey. Serum lipid profiles included total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A (APO-A), and apolipoprotein B (Apo-B). The joint effect of smoking and BMI on serum lipids were examined by the four-way decomposition analysis and multivariate linear regression models. RESULTS: The four-way decomposition showed that the interplay between smoking and BMI was complicated. There was only indirect effect (the mediated effect) between smoking and BMI on TC, LDL-C and APO-B. The pure indirect effect was -0.023 for TC, -0.018 for LDL-C, and -0.009 for APO-B. For TG, HDL-C and APO-A, the interaction effect was dominant. The reference interaction (the interactive effect when the mediator is left to what it would be in the absence of exposure) was 0.474 (P < 0.001) for TG, -0.245 (P = 0.002) for HDL-C, and -0.222 (P < 0.001) for APO-A, respectively. The effect of BMI on TG, HDL-C and APO-A were significantly higher in smokers than in nonsmokers (TG: 0.151 in smokers versus 0.097 in nonsmokers, HDL-C: -0.037 versus -0.027, APO-A: -0.019 versus -0.009, P for difference < 0.001 for all). CONCLUSION: These findings illustrate the joint effects of smoking and BMI on serum lipid profiles. There were significant interaction effects of smoking and BMI on TG, HDL-C and APO-A, while BMI maybe a mediator for the association of smoking with TC, LDL-C and APO-B. The effects between them were rather complex. Smoking cessation is necessary, especially for those overweight.

Temporal sequence of blood lipids and insulin resistance in perimenopausal women: the study of women's health across the nation.

INTRODUCTION: To explore the temporal relationship between blood lipids and insulin resistance in perimenopausal women. RESEARCH DESIGN AND METHODS: The longitudinal cohort consisted of 1386 women (mean age 46.4 years at baseline) in the Study of Women's Health Across the Nation. Exploratory factor analysis was used to identify appropriate latent factors of lipids (total cholesterol (TC); triglyceride (TG); high-density lipoprotein cholesterol (HDL-C); low-density lipoprotein cholesterol (LDL-C); lipoprotein A-I (LpA-I); apolipoprotein A-I (ApoA-I); apolipoprotein B (ApoB)). Cross-lagged path analysis was used to explore the temporal sequence of blood lipids and homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Three latent lipid factors were defined as: the TG factor, the cholesterol transport factor (CT), including TC, LDL-C, and ApoB; the reverse cholesterol transport factor (RCT), including HDL-C, LpA-I, and ApoA-I. The cumulative variance contribution rate of the three factors was 86.3%. The synchronous correlations between baseline TG, RCT, CT, and baseline HOMA-IR were 0.284, -0.174, and 0.112 (p<0.05 for all). After adjusting for age, race, smoking, drinking, body mass index, and follow-up years, the path coefficients of TG→HOMA-IR (0.073, p=0.004), and HOMA-IR→TG (0.057, p=0.006) suggested a bidirectional relationship between TG and HOMA-IR. The path coefficients of RCT→HOMA-IR (-0.091, P < 0.001) and HOMA-IR→RCT (-0.058, p=0.002) were also significant, but the path coefficients of CT→HOMA-IR (0.031, p=0.206) and HOMA-IR→CT (-0.028, p=0.113) were not. The sensitivity analyses showed consistent results. CONCLUSIONS: These findings provide evidence that TG and the reverse cholesterol transport-related lipids are related with insulin resistance bidirectionally, while there is no temporal relationship between the cholesterol transport factor and insulin resistance.

Four-Way Decomposition of Effect of Alcohol Consumption and Body Mass Index on Lipid Profile.

Background: Both obesity and alcohol consumption are strongly associated with dyslipidemia; however, it remains unclear whether their joint effect on lipid profiles is through mediation, interaction, or a combination of the two. Methods: In total, 9849 subjects were selected from the 2009 panel of China Health and Nutrition Survey (CHNS). A four-way decomposition method was used to validate the pathways of drinking and body mass index (BMI) on lipids (total cholesterol, TC; triglyceride, TG; low-density lipoprotein cholesterol, LDL-C; high-density lipoprotein cholesterol, HDL-C; apolipoprotein A, APO-A; and apolipoprotein B, APO-B). Results: According to four-way decomposition, the total effects of drinking on lipids were found to be statistically significant, except for LDL-C. The components due to reference interaction were 0.63, 0.48, 0.60, -0.39, -0.30, and 0.20 for TC, TG, LDL-C, HDL-C, APO-A and APO-B, respectively (p < 0.05 for all). The effect size of pure indirect effect and mediated interaction were 0.001~0.006 (p > 0.05 for all). Further, linear regression models were used to examine the effect of BMI on lipid profiles in drinkers and non-drinkers. The associations of BMI and lipids were higher in all drinkers than in non-drinkers (0.069 versus 0.048 for TC, 0.079 versus 0.059 for TG, 0.057 versus 0.037 for LDL-C, -0.045 versus -0.029 for HDL-C, -0.024 versus -0.011 for APO-A and 0.026 versus 0.019 for APO-B, p interaction <0.05 for all). Conclusions: The joint effect of alcohol consumption and obesity on lipid profiles is through interaction rather than mediation. Alcohol consumption amplifies the harmful effect of BMI on lipid profiles. Greater attention should be paid to lipid health and cardiovascular risk in obese individuals regarding alcohol consumption. For obese individuals, we do not recommend alcohol consumption.

Serum metabolomics analysis for the progression of esophageal squamous cell carcinoma.

BACKGROUND: Previous metabolomics studies have found differences in metabolic characteristics between the healthy and ESCC patients. However, few of these studies concerned the whole process of the progression of ESCC. This study aims to explore serum metabolites associated with the progression of ESCC. METHODS: Serum samples from 653 participants (305 normal, 77 esophagitis, 228 LGD, and 43 HGD/ESCC) were examined by ultra-high performance liquid chromatography quadruple time-of-flight mass spectrometry (UHPLC-QTOF/MS). Principal component analysis (PCA) was first applied to obtain an overview of the clustering trend for the multidimensional data. Fuzzy c-means (FCM) clustering was then used to screen metabolites with a changing tendency in the progression of ESCC. Univariate ordinal logistic regression analysis and multiple ordinal logistic regression analysis were applied to evaluate the association of metabolites with the risk of ESCC progression, and adjusted for age, gender, BMI, tobacco smoking, and alcohol drinking status. RESULTS: After FCM clustering analysis, a total of 38 metabolites exhibiting changing tendency among normal, esophagitis, LGD, and HGD/ESCC patients. Final results showed 15 metabolites associated with the progression of ESCC. Ten metabolites (dopamine, L-histidine, 5-hydroxyindoleacetate, L-tryptophan, 2'-O-methylcytidine, PC (14:0/0:0), PC (O-16:1/0:0), PE (18:0/0:0), PC (16:1/0:0), PC (18:2/0:0)) were associated with decreased risk of developing ESCC. Five metabolites (hypoxanthine, inosine, carnitine (14:1), glycochenodeoxycholate, PC (P-18:0/18:3)) were associated with increased risk of developing ESCC. CONCLUSIONS: These results demonstrated that serum metabolites are associated with the progression of ESCC. These metabolites are capable of potential biomarkers for the risk prediction and early detection of ESCC.

The mediation effect of serum metabolites on the relationship between long-term smoking exposure and esophageal squamous cell carcinoma.

BACKGROUND: Long-term smoking exposure will increase the risk of esophageal squamous cell carcinoma (ESCC), whereas the mechanism is still unclear. We conducted a cross-sectional study to explore whether serum metabolites mediate the occurrence of ESCC caused by cigarette smoking. METHODS: Serum metabolic profiles and lifestyle information of 464 participants were analyzed. Multiple logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of smoking exposure to ESCC risk. High-dimensional mediation analysis and univariate mediation analysis were performed to screen potential intermediate metabolites of smoking exposure for ESCC. RESULTS: Ever smoking was associated with a 3.11-fold increase of ESCC risk (OR = 3.11, 95% CI 1.63-6.05), and for each cigarette-years increase in smoking index, ESCC risk increased by 56% (OR = 1.56, 95% CI 1.18-2.13). A total of 5 metabolites were screened as mediators by high-dimensional mediation analysis. In addition, glutamine, histidine, and cholic acid were further proved existing mediation effects according to univariate mediation analysis. And the proportions of mediation of histidine and glutamine were 40.47 and 30.00%, respectively. The mediation effect of cholic acid was 8.98% according to the analysis of smoking index. CONCLUSIONS: Our findings suggest that cigarette smoking contributed to incident ESCC, which may be mediated by glutamine, histidine and cholic acid.

Trajectories of early to mid-life adulthood BMI and incident diabetes: the China Health and Nutrition Survey.

INTRODUCTION: This longitudinal study aims to characterize distinct body mass index (BMI) trajectories during early to mid-life adulthood and to explore the association between BMI change from young adulthood to midlife and incident diabetes. RESEARCH DESIGN AND METHODS: This study included 7289 adults who had repeatedly measured BMI 3-9 times during 1989-2011 and information on incident diabetes. Latent class growth mixed model (LCGMM) was used to identify different BMI trajectories. Cox proportional hazard models were used to investigate the association between the trajectory group membership and incident hyperglycemia, adjusting for covariates. The hyperglycemia group included individuals with prediabetes or diabetes. The model-estimated BMI levels and slopes were calculated at each age point in 1-year intervals according to the model parameters and their first derivatives, respectively. Logistic regression analyses were used to examine the association of model-estimated levels and slopes of BMI at each age point with incident hyperglycemia. The area under the curve (AUC) was computed from longitudinal growth curve models during the follow-up for each individual. Prior to the logistic regression analyses, quartiles of total, baseline, and incremental AUC values were calculated. RESULTS: Three distinct trajectories were characterized by LCGMM, comprising of low-increasing group (n=5136), medium-increasing group (n=1914), and high-increasing group (n=239). Compared with the low-increasing group, adjusted HRs and 95% CIs were 1.21 (0.99 to 1.48) and 1.56 (1.06 to 2.30) for the medium-increasing and the high-increasing group, respectively. The adjusted standardized ORs of model-estimated BMI levels increased among 20-50 years, ranging from 0.98 (0.87 to 1.10) to 1.19 (1.08 to 1.32). The standardized ORs of level-adjusted linear slopes increased gradually from 1.30 (1.16 to 1.45) to 1.42 (1.21 to 1.67) during 20-29 years, then decreased from 1.41 (1.20 to 1.66) to 1.20 (1.08 to 1.33) during 30-43 years, and finally increased to 1.20 (1.04 to 1.38) until 50 years. The fourth quartile of incremental AUC (OR=1.31, 95% CI 1.03 to 1.66) was significant compared with the first quartile, after adjustment for covariates. CONCLUSIONS: These findings indicate that the BMI trajectories during early adulthood were significantly associated with later-life diabetes. Young adulthood is a crucial period for the development of diabetes, which has implications for early prevention.

Allyl methyl trisulfide protected against acetaminophen (paracetamol)-induced hepatotoxicity by suppressing CYP2E1 and activating Nrf2 in mouse liver.

In order to investigate the protective effects of allyl methyl trisulfide (AMTS) on acetaminophen (APAP)-induced hepatotoxicity, 75 KM mice were randomized into 5 groups, i.e. a control group, an APAP group, and three AMTS/APAP groups. The mice in the AMTS/APAP groups and APAP group were gavaged with 25-100 mg kg-1 AMTS or corn oil for 7 d followed by intraperitoneal injection of 300 mg kg-1 APAP, while mice in the control group were treated with a vehicle. We found that AMTS significantly attenuated APAP-induced hepatotoxicity shown by reduced mortality, decreased serum aminotransferase activities, and improved liver histological morphology. APAP overdose resulted in a significant increase of hepatic malondialdehyde (MDA) level and a decrease of the protein levels of NQO-1, γ-GCS, HO-1, and SOD, which was suppressed by AMTS pretreatment. Furthermore, AMTS inhibited the APAP-induced elevation of hepatic p62 and LC3II protein levels. Interestingly, AMTS attenuated the APAP-induced decline of hepatic CYP2E1 protein levels, but AMTS alone led to the decrease of CYP2E1 protein expression in mouse liver. Collectively, these data suggest that AMTS could attenuate APAP-induced hepatotoxicity by suppressing CYP2E1 and activating Nrf2.

Obtaining amplitude-modulated bursting by multiple-frequency slow parametric modulation.

Amplitude-modulated bursting (AMB), characterized by oscillations appearing in the envelope of the active phase of bursting, is a novel class of bursting rhythms reported recently. The present paper aims to report a simple and effective method, i.e., the multiple-frequency slow parametric modulation (MFSPM) method, for obtaining such a bursting pattern. We show that the MFSPM can be well controlled so that it may exhibit multiple continuous ups and downs in the active area. Then, the amplitude of the traced active state alternates between increases and decreases accordingly, which leads to oscillations in the envelope of the active phase, and AMB is thus created. Based on this, the route to AMB by the MFSPM is presented. The validity of the approach is demonstrated by several examples. The proposed approach does not depend on specific systems or bifurcations and thus is a general method.